Erythropoiesis is sensitive to the local environment such as oxygen tension. Decreasing oxygen tension of erythropoietin stimulated human hematopoietic progenitor cells decreased proliferation and increased fetal hemoglobin production at physiologic oxygen tension, which then decreased when oxygen tension approached cytotoxic low levels. Increasing erythropoietin concentration of differentiating human erythroid progenitor cells increased glucose uptake accompanying the increase in cell proliferation and number of hemoglobin positive cells, although no change in fetal hemoglobin induction was observed. These studies provide evidence for the energy burden of increased erythropoietin stimulated erythropoiesis and resultant metabolic activity of erythroid cells, and indicates that erythropoietin administration alone is not sufficient to alter fetal hemoglobin production. The increased cell metabolic activity of erythropoietin stimulated erythropoiesis was also observed in vivo. Mice treated with erythropoietin exhibited decreased blood glucose accompanying the increased hematocrit. Change in blood glucose level is a direct consequence of erythropoietin stimulated erythroid cell response as the decrease in blood glucose was also observed in mice with erythropoietin receptor restricted to erythroid cells. For treatment of sickle cell disease, hydroxyurea, an inducer of fetal hemoglobin, is the only approved therapy. Other modes of hydroxyurea action beyond direct increase in fetal hemoglobin have been suggested including increasing nitric oxide, increasing red blood cell water content, and altering cell adhesion to the endotheium. Manipulation of non-erythroid cells in the bone marrow microenvironment has the potential to influence hematopoiesis and erythroid differentiation. Studies of hematological malignancies suggest that angiogenesis contributes importantly to development of disease and expression of corresponding angiogenic factors. We observed that in myeloproliferative neoplasms CD34+ cells show enhanced expression of angiogenic factors while hydroxyurea therapy reduced angiogenic factors expression in granulocytes, suggesting that that hydroxyurea response in non-erythroid cells may affect the bone marrow microenvironment and contribute to overall response. Erythropoietin is produced in the kidney in a hypoxia inducible manner. As a therapeutic, erythropoietin has been used for more than two decades to treat anemia in end stage renal disease that results from disrupted erythropoietin production. We found in a retrospective cohort study of hemodialysis patients with end stage renal disease that erythropoietin administered intravenously resulted in 25% higher erythropoietin dose and greater risk of death and hospitalization for cardiovascular complications compared with subcutaneous administration. This relates to the rapid clearance of circulating exogenous erythropoietin and the slower release into the circulation with subcutaneous erythropoietin administration. While intravenous administration is the standard practice for patients on hemodialysis relating to ease of use, subcutaneous erythropoietin administration is associated with more favorable clinical outcomes.